Patent GB-756471-A (GB)
Title: A process for the production of new derivatives of barbituric acid
Filed: 1954-03-03
Abstract: Mixtures of D 1,2- and D 2,3-cyclo-octenyl-barbituric and thiobarbituric acid derivatives of the general formula <FORM:0756471/IV(a)/1> in which X is an alkyl or alkenyl group, Y is an alkyl group or hydrogen and Z is a D 1,2- or D 2,3-cyclo-octenyl radical, are prepared by condensing (a) cyclo-octanone, preferably in the presence of glacial acetic acid and of amides (such as acetamide or formamide), amines (such as piperidine), or alkali metal acetates, or (b) 1,2-dibromo-cyclo-octane or 1-bromo-D 2,3-cyclo-octene in the presence of a strong base (such as sodium alcoholate), with a barbituric or thiobarbituric acid which may contain in the positions 3 and/or 5 the above-defined alkyl or alkenyl substituents Y and X, or with malonic acid esters, malodinitriles or cyano acetic acid esters which may contain the alkyl or alkenyl substituent X followed by condensation of the C-cyclo-octenyl-malonic esters, -malodinitriles or -cyanoacetic acid esters respectively obtained (which if they do not already contain the group X may be alkylated or alkenylated by means of alkyl or alkenyl halides or sulphates) with urea, thiourea, cyanamide, dicyandiamide or guanidine, which may contain at one of their N atoms the alkyl substituent Y, and, if said guanidines, cyanamides or dicyandiamides and/or malodinitrile or cyano acetic acid esters are used, saponifying the 2- and/or 4-imino barbituric acid derivatives formed (which when using cyanamide or dicyandiamides, will contain a cyano group in position 1) by boiling them with dilute mineral acids, and then alkylating or alkenylating the barbituric acid or thiobarbituric acid derivatives obtained by means of alkyl or alkenyl halides or sulphates if they do not yet contain the alkyl and/or alkenyl groups X and Y.  In reaction (b) the alkali metal derivatives of the barbituric acids or of the malonic acid or cyanoacetic acid esters or malodinitriles are advantageously used and when using 1,2-dibromo-cyclo-octane twice the equivalent amount of a basic condensing agent, e.g. sodium ethylate, is preferably used.  In examples: (1) cyclo-octanone and cyanoacetic acid ethyl ester in the presence of acetamide and glacial acetic acid give D 1,2-cyclo-octenyl-cyano acetic acid ethyl ester; this with ethyl bromide in ethanol with sodium gives ethyl-(D 11,21-cyclo-octenyl)-cyano acetic acid ethyl ester which is then condensed with urea in ethanol with sodium to give 4-imino-5-ethyl-5-(D 11,21-cyclo-octenyl)-barbituric acid, and this on hydrolysis gives 5 - ethyl - 5 - (D 11,21 - cyclo-octenyl)-barbituric acid; the use of n-propyl bromide and n-butyl chloride in the second stage of the above reaction sequence is also referred to; (2) methyl malonic acid diethyl ester and 1 - bromo - D 2,3 - cyclo - octene in ethanol with sodium give methyl-(D 2,3-cyclo-octenyl)-malonic acid diethyl ester which upon condensation with dicyandiamide in methanol with sodium gives 1 - cyano - 2 - imino - 5 - methyl - 5 - (D 21,31 - cyclo - octenyl) - barbituric acid; on hydrolysis this yields 5-methyl-5-(D 21,31-cyclo-octenyl)-barbituric acid or on methylation with dimethyl sulphate it gives 1-cyano-2-imino-3,5-dimethyl - 5 - (D 21,31 - cyclo - octenyl) - barbituri acid which on hydrolysis yields 3,5-dimethyl-5-(D 21,31 - cyclo - octenyl) - barbituric acid; (3) sodium ethylmalonic acid diethyl ester and 1,2-dibromo-cyclo-octane with sodium alcoholate in alcohol give ethyl-(D 2,3-cyclo-octenyl)-malonic acid diethyl ester which on condensation with thiourea in alcohol with sodium gives 5 - ethyl - 5 - (D 21,31 - cyclo - octenyl) - thiobarbituric acid; the corresponding urea derivative is prepared similarly; (4) 5-monoethyl-barbituric acid and 1-bromo-D 2,3-cyclo-octene in ethanol with caustic potash give 5-(D 21,31-cyclo-octenyl)-5-ethyl-barbituric acid.